The present invention describes novel methods to induce synthesis of endogenous nitric oxide or endothelium-derived relaxing factor, and methods for maintaining levels of nitric oxide under hypoxic conditions. One aspect of the invention relates to novel methods to induce vasodilation. The present invention also provides methods for treating or preventing sexual dysfunctions in males and females by administering at least one N-hydroxyguanidine compound, such as N-hydroxy-L-arginine, and, optionally, one or more vasoactive agents and/or thromboxane A2 receptor antagonists. The present invention also provides methods for treating clinical conditions resulting from hypoxic conditions, such as, pulmonary diseases, cardiovascular disorders, circulatory hypoxia, specific organ hypoxia, localized hypoxia, edema, central nervous system disorders, memory loss and/or arterial disease. The present invention also provides methods for treating clinical conditions resulting from an abnormally high level of arginase activity, such as, heart diseases, systemic hypertension, pulmonary hypertension, sexual dysfunctions, autoimmune diseases, chronic renal failure and/or cerebral vasospasm. The present invention also provides methods for treating clinical conditions associated with a deficient nitric oxide pathway by administering at least one N-hydroxyguanidine compound, and, optionally, one or more vasoactive agents and/or thromboxane A2 receptor antagonists. The present invention also provides novel compositions comprising at least one N-hydroxyguanidine, and optionally, one or more vasoactive agents and/or thromboxane A2 receptor antagonists. The N-hydroxyguanidine compounds in the present invention are substrates for nitric oxide synthase.
Nitric oxide is a small diatomic molecule with multiple biological actions, including inhibition of platelet adhesion and aggregation, and relaxation of vascular and non-vascular smooth muscles. Nitric oxide has also been reported to have antiinflammatory, anti-bacterial and anti-viral properties (Moncada et al, Pharmacol Rev. 43:109-142 (1991)). In the gaseous state nitric oxide exists as a lipophilic molecule in a neutral redox state (NO). Nitric oxide is a complex molecule since it is able to exist in multiple redox states under different physiological conditions. It can also formally exist in charged forms i.e., nitrosonium (NO+) or nitroxyl (NOxe2x88x92), or as the neutral species, nitric oxide (NOxe2x80xa2). In biological tissues, nitric oxide has a very short half-life, estimated at less than one second.
One of the potent actions of nitric oxide in mammals is to relax vascular and non-vascular tissue, and, as such, either nitric oxide or an adduct that delivers nitric oxide, is useful as a vasodilator. In the mammalian body, endogenous nitric oxide is produced through an enzymatic reaction in which nitric oxide synthases utilize L-arginine and molecular oxygen for the synthesis of nitric oxide and citrulline. One of the actions of nitric oxide is believed to be the activation of a soluble form of guanylate cyclase, a cellular enzyme, which catalyses the formation of 3xe2x80x2,5xe2x80x2-cyclic guanosine monophosphate (cGMP). The cGMP is believed to act on other cellular targets to mediate the relaxation of vascular smooth muscle and provide the therapeutic effect of vasodilation. Another action of nitric oxide is believed to be the regulation of Na(+)-K(+)-ATPase.
The synthesis of nitric oxide from L-arginine by nitric oxide synthase occurs in two steps, each of which requires NADPH. In the first step, an intermediate N-hydroxyguanidine product, NG-hydroxy-L-arginine, is synthesized by the incorporation of an oxygen into the guanidine function of the L-arginine molecule. In the second step, a second oxygen is incorporated into NG-hydroxy-L-arginine to form L-citrulline and nitric oxide. (Fukuto et al, in Methods in Nitric Oxide Research, Feelisch et al, eds., John Wiley and Sons, Ltd., pp. 147-160 (1996)). Under an environment of low oxygen tension, however, the synthesis of nitric oxide is greatly reduced. (Furchgott et al, Nature, 288(5789):373-376 (1980); Johns et al, Circ. Res., 65(6):1508-1515 (1989)).
Several clinical conditions are associated with low oxygen tension, such as sexual dysfunctions (Kim et al, J. Clin. Invest. 91(2):437-442 (1993)), pulmonary diseases (including respiratory distress syndrome, asthma, bronchitis/emphysema, and chronic obstructive pulmonary disease) (Howes et al, Thorax, 51(5):516-519, (1996); Fagan et al, Biochem. Biophys. Res. Commun. 254(1):100-103 (1999)), circulatory hypoxia (including heart failure, strokes, and shock), specific organ hypoxia (in which decreased circulation to a specific organ resulting in localized circulatory hypoxia can be due to organic arterial obstruction or can result as a consequence of vasoconstriction, e.g., Raynaud""s Syndrome) (Agusti et al, Eur. Rspir. J. 10(9):1962-1966 (1997)), localized hypoxia (which can result from venous obstruction and resultant congestions and reduced arterial blood inflow), edema (which increases the distance through which oxygen diffuses before it reaches the cells can also cause localized hypoxia), central nervous system disorders, memory loss, and arterial disease (Weitzberg et al, Acta. Physiol. Scand. 143(4):451-452 (1991)).
Respiratory distress syndrome, in a child or adult, has severe consequences in the vasculature, such as pulmonary hypertension. Arterial insufficiency of the blood vessel of the penis leads to hypoxic ischemia of this tissue, which limits the synthesis of nitric oxide and, therefore, limits the erectile capacity.
Increased oxygen requirements can also lead to low oxygen tension. For example, if the oxygen consumption of a tissue is elevated without a corresponding increase in volume flow per unit time, then the oxygen tension (PaO2) in the venous blood can be reduced. This can also occur when the hemoglobin is qualitatively and quantitative normal. Examples of such situations include fever and thyrotoxicosis in which cardiac output cannot rise normally, and also in cases in which metabolic rates of oxygen consumption are high.
It would be desirable to increase the production of nitric oxide in tissue under low oxygen conditions to activate the chain of biochemical and cellular events that lead to vasodilation. The present invention is directed to these, as well as other, important ends.
It has been discovered that administering one or more N-hydroxyguanidine compounds that are substrates for nitric oxide synthase, such as N-hydroxy-L-arginine, to tissues under conditions of low oxygen tension (hypoxia), results in the synthesis of nitric oxide, which is more effective than arginine in promoting the formation of cGMP and the relaxation of vascular and non-vascular smooth muscles.
One embodiment of the invention provides methods of promoting synthesis of nitric oxide in vascular and non-vascular cells of a mammal under low oxygen conditions comprising administering to the mammal a therapeutically effective amount of at least one N-hydroxyguanidine compound, such as N-hydroxy-L-arginine, and, optionally, at least one vasoactive agent and/or at least one thromboxane A2 receptor antagonist.
Another embodiment of the invention provides methods of promoting relaxation of vascular and non-vascular smooth muscle in a mammalian tissue under low oxygen conditions comprising administering to the patient a therapeutically effective amount of at least one N-hydroxyguanidine compound, such as N-hydroxy-L-arginine, and, optionally, at least one vasoactive agent and/or at least one thromboxane A2 receptor antagonist.
Another embodiment of the invention provides methods of treating sexual dysfunctions in patients, including males and females, comprising administering to the patient a therapeutically effective amount of at least one N-hydroxyguanidine compound, such as N-hydroxy-L-arginine, and, optionally, at least one vasoactive agent and/or at least one thromboxane A2 receptor antagonist. Generally, the sexual dysfunction is attributable to low oxygen conditions. Preferably, the sexual dysfunctions are attributable to hypoxic ischemia, neuropathy or arterial disease.
Another embodiment of the invention provides methods of promoting synthesis of nitric oxide or endothelium-derived relaxing factor (EDRF) in hypoxic mammalian cells (low oxygen conditions) comprising administering to the patient a therapeutically effective amount of at least one N-hydroxyguanidine compound, such as N-hydroxy-L-arginine, and, optionally, at least one vasoactive agent and/or at least one thromboxane A2 receptor antagonist.
Another embodiment of the invention provides methods to treat clinical conditions associated with low oxygen tension, such as, pulmonary diseases, circulatory hypoxia, specific organ hypoxia, localized hypoxia, edema, central nervous system disorders, memory loss or arterial disease, comprising administering to a patient in need thereof a therapeutically effective amount of at least one N-hydroxyguanidine compound, such as N-hydroxy-L-arginine, and, optionally, at least one vasoactive agent and/or at least one thromboxane A2 receptor antagonist.
Another embodiment of the invention provides methods to treat clinical conditions associated with an abnormally high level of arginase activity, such as, heart disease, systemic hypertension, sexual dysfunctions, pulmonary hypertension, autoimmune diseases, chronic renal failure and cerebral vasospasm, comprising administering to a patient in need thereof a therapeutically effective amount of at least one N-hydroxyguanidine compound, such as N-hydroxy-L-arginine, and, optionally, at least one vasoactive agent and/or at least one thromboxane A2 receptor antagonist.
Another embodiment of the invention provides methods to promote the synthesis of nitric oxide or endothelium-derived relaxing factor in mammals with deficient nitric oxide pathways comprising administering to the patient a therapeutically effective amount of at least one N-hydroxyguanidine compound, such as N-hydroxy-L-arginine, and, optionally, at least one vasoactive agent and/or at least one thromboxane A2 receptor antagonist.
Another embodiment of the invention provides therapeutic compositions comprising at least one N-hydroxyguanidine compound, such as N-hydroxy-L-arginine, and a pharmaceutically acceptable carrier, and, optionally, at least one vasoactive agent and/or at least one thromboxane A2 receptor antagonist. The compositions can also comprise an analog of N-hydroxy-L-arginine, and/or other active compounds.
These and other aspects of the present invention are described in more detail herein.